Review Article RolesforEndothelialCellsinDengueVirusInfection · 2019. 7. 31. · DHF and DSS are severe manifestations of dengue virus infection that result in increased vascular

Hindawi Publishing CorporationAdvances in VirologyVolume 2012, Article ID 840654, 8 pagesdoi:10.1155/2012/840654

Review Article

Roles for Endothelial Cells in Dengue Virus Infection

Nadine A. Dalrymple and Erich R. Mackow

Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794-5222, USA

Correspondence should be addressed to Erich R. Mackow, [email protected]

Received 20 January 2012; Accepted 19 July 2012

Academic Editor: Sujan Shresta

Copyright © 2012 N. A. Dalrymple and E. R. Mackow. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Dengue viruses cause two severe diseases that alter vascular fluid barrier functions, dengue hemorrhagic fever (DHF) and dengueshock syndrome (DSS). The endothelium is the primary fluid barrier of the vasculature and ultimately the effects of denguevirus infection that cause capillary leakage impact endothelial cell (EC) barrier functions. The ability of dengue virus to infect theendothelium provides a direct means for dengue to alter capillary permeability, permit virus replication, and induce responses thatrecruit immune cells to the endothelium. Recent studies focused on dengue virus infection of primary ECs have demonstrated thatECs are efficiently infected, rapidly produce viral progeny, and elicit immune enhancing cytokine responses that may contribute topathogenesis. Furthermore, infected ECs have also been implicated in enhancing viremia and immunopathogenesis within murinedengue disease models. Thus dengue-infected ECs have the potential to directly contribute to immune enhancement, capillarypermeability, viremia, and immune targeting of the endothelium. These effects implicate responses of the infected endotheliumin dengue pathogenesis and rationalize therapeutic targeting of the endothelium and EC responses as a means of reducing theseverity of dengue virus disease.

1. Introduction

Dengue viruses are transmitted by mosquitoes and infect∼50 million people annually with an additional 2.5 billionpeople at risk living in tropical areas [1–3]. Expandingmosquito habitats are increasing the range of dengue virusoutbreaks and the occurrence of severe diseases with 5–30%mortality rates: dengue hemorrhagic fever (DHF) and den-gue shock syndrome (DSS) [1–3]. The majority of patientsare asymptomatic or display mild symptoms of denguefever (DF) which include rapid onset of fever, viremia,headache, pain, and rash [4]. Patients with DHF and DSSdisplay symptoms of DF in addition to increased edema,hemorrhage, thrombocytopenia, and shock [1–3]. Althoughpatient progression to DHF and DSS is not fully understood[3, 5], antibody-dependent enhancement (ADE) of dengueinfection increases the potential for DSS and DHF [3, 6,7]. There are four dengue virus serotypes (types 1–4) andinfection by one serotype predisposes individuals to moresevere disease following a subsequent infection by a differentdengue serotype. The circulation of serotype-specific cross-reactive antibodies or preexisting maternal antibodies may

contribute to progression to DHF/DSS by facilitating viralinfection of immune cells and eliciting cytokine and chemo-tactic immune responses. In a murine antibody dependentenhancement model of dengue disease it was observed that adramatic increase in infected hepatic endothelial cells (ECs)coincides with the onset of severe disease [8] and suggestsa role for the endothelium in an immune-enhanced diseaseprocess during dengue infection.

The major target tissues for dengue virus infection havebeen difficult to determine but virus has been isolated fromhuman blood, lymph node, bone marrow, liver, heart, andspleen [9–14]. Blood samples are more easily obtained fromdengue patients than tissues and yield a wide array ofinformation about cytokine responses elicited by denguevirus infection [1–3, 14–18]. While many of these cytokinesare present in DF patients, the majority of them are increasedduring DHF. Overall, DHF responses include greater cy-tokine production, T- and B-cell activation, complementactivation, and T-cell apoptosis [3]. Complement pathwayactivation and elevated levels of complement proteins C3,C3a, and C5a are significant in that they can direct opsoniza-tion, chemotaxis of mast and other immune cells, and direct

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the localized release of the vascular permeability factor his-tamine from mast cells [17, 19–23]. Importantly, cytokinesand complement factor responses all act on the endotheliumand alter normal fluid barrier functions of ECs.

The ability of dengue virus to infect immune, dendritic,and endothelial cells fosters a role for immune responses toact on the endothelium and increase capillary permeability[5, 24–29]. However, the redundant nature of capillarybarrier functions suggests that permeability is likely tobe multifactorial in nature with many factors working inconcert to modulate EC responses and permeabilize theendothelium. Dengue infected ECs are observed in DHF/DSSpatient autopsy samples and in murine dengue virus diseasemodels [8, 9, 14, 30]. This suggests that dengue infected ECsmay also contribute directly to pathogenesis by increasingviremia, secreting cytokines, modulating complement path-ways, or transforming the endothelium into an immunologictarget of cellular and humoral immune responses.

Plasma constituents contain factors secreted by an esti-mated ∼1013 ECs present in the body, and autopsy samplesand murine dengue disease models clearly demonstrate thatvascular ECs are infected [8, 9, 30, 31]. The endotheliumis the primary fluid barrier of the vasculature and denguevirus-induced responses resulting in edema or hemorrhagicdisease ultimately cause changes in EC permeability. UniqueEC receptors, adherens junctions, and signaling pathwaysrespond to cytokines, permeability factors, immune com-plexes, clotting factors, and platelets, normally acting in con-cert to control vascular leakage [5, 32–36]. Virally inducedchanges in endothelial or immune cell responses have thepotential to alter this orchestrated balance with pathologicconsequences [5, 32–35]. However, very little is known aboutthe role of dengue virus-infected ECs in disease or thekinetics, timing, and replication of dengue viruses withinpatient ECs. The inability to kinetically study the endothe-lium in dengue patients and the relative ease of assessingblood components has resulted in a focus on immune cellsinstead of ECs. Yet, the endothelium is the ultimate target ofpermeabilizing responses. Here, we discuss studies of dengueinfected ECs and the potential for the dengue infectedendothelium to contribute to dengue pathogenesis.

2. Human Responses to Dengue Virus Infection

DHF and DSS are severe manifestations of dengue virusinfection that result in increased vascular permeability,hemorrhage, and shock [3]. The presence of preexistingantibodies to dengue virus predisposes patients to severedisease following infection by a second dengue serotype[3]. A myriad of responses are associated with dengueinfection that may contribute to disease, but the pathogenicmechanisms that result in DHF and DSS remain ambiguous[1–3, 26]. One common element of the dengue diseaseprocess is that enhanced immune responses increase vascularpermeability by acting on the endothelium. Although itis clear that immune cells and their responses contributeto pathogenesis, the endothelium, which regulates vascularleakage, has not been considered a significant component ofDHF and DSS [2, 5, 34, 35, 37].

2.1. Patient Studies. The ability of dengue virus to infecthuman ECs has been documented in autopsy samples ofthe heart, liver, and lung [9, 14]. In a postmortem study,Jessie et al. reported dengue virus antigen in sinusoidal ECsin the liver as well as macrophages, lymphoid cells in thespleen, the vascular endothelium of the lung, monocyteswithin the blood, and kidney tubules [9]. Salgado et al. alsodemonstrated the presence of viral antigen in endothelialcells within the heart and small myocardial vessels of apatient postmortem [14]. Depressed myocardial function hasbeen associated with hemorrhagic forms of dengue virusinfection [38]. Although no dengue virus RNA was detectedin these cells by in situ hybridization, viral antigen uptake wasalso not confirmed. Additionally, no morphological damageto the endothelium was observed that might explain vascularleakage through disruption of the endothelium. However, thepresence of circulating ECs, EC markers (VCAM and ICAM),and increased von Willebrand factor antigen and procoag-ulants, specifically in DHF patients, has been reported inother cases [39, 40]. Nevertheless, autopsy samples do nottake into account contributions of dengue virus infection ofECs at earlier time points that may contribute to viremiaand immune enhancing responses. Kinetic analysis of theendothelium in patients is invasive and has not beenaddressed. In general, little clinical data has been obtainedbetween viral inoculation and onset of fever and viremia[3]. Thus, findings that ECs are infected with dengue havebeen marginalized since immune enhancing responses arepresumed to be derived solely from immune cells. However,a variety of mechanisms exist for ECs to elicit immuneenhancing cytokine and complement responses that recruitimmune cells to the endothelium or directly alter barrierfunctions of EC adherens junctions [3–5, 41]. Finding thatECs are infected in patients suggests a direct means by whichthe infected endothelium may be altered by dengue virus.Additionally, preexisting antibodies may target DV anti-gen within infected ECs, further contributing to immune-enhanced permeability deficits observed in DHF and DSS.

2.2. Patient Responses to Infection and Markers of DHF/DSS.A hallmark of severe dengue disease is the presence ofelevated levels of cytokines and chemokines including IP-10, ITAC, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12, IL-13, TNFα,IFNα, IFNγ, MIF, RANTES, histamine, and complementproteins C3, C3a, and C5a within blood and tissues [1–3, 14–18]. In patients, complement activation and an increase incomplement protein products correlate with the severity ofdisease [42–45]. In a study by Avirutnan et al., C5b-9 com-plexes, complement-activated membrane-attack complexes,and C3a were formed on dengue-infected ECs in the presenceof antibody—containing immune serum, though they didnot direct complement-mediated cell lysis [26]. C3a is ananaphylatoxin that recruits mast cells and directs histaminerelease that locally increases vascular permeability [17, 19–22]. Elevated C3a, C5a, and histamine have been associatedwith severe permeability deficits in dengue virus patientsand in the development of DHF and DSS [2, 3, 17, 26, 42].Their presence in the blood of patients with severe denguedisease is significant since these anaphylatoxins direct lysis

Advances in Virology 3

of infected cells and mast cell degranulation, leading tohistamine release.

Importantly, cytokines, chemokines, and complement-activating factors can all be secreted by and act on theendothelium, influencing EC regulation of fluid barrierfunction and vascular leakage [5, 32–35]. The ability ofdengue virus to infect the endothelium intimates that addi-tional mechanisms could contribute to vascular permeabilitydeficits through both direct- and immune-enhanced diseaseprocesses. Dengue infected ECs may elicit chemokine andcytokine responses that further activate or recruit immunecells to the endothelium and preexisting dengue antibodiesmay target viral proteins displayed on infected endothelium.Recent analysis of primary EC transcriptional responses indi-cates that dengue virus strongly induces secretion of immunecell activating cytokines, chemokines, and complementfactors that are likely to contribute to an immune enhanceddisease process [46]. Since permeability is ultimately theresult of responses that act on the endothelium, dengueinfected ECs are key elements in DSS and DHF that mustbe considered more fully within animal and in vitro models.

2.3. Roles of NS1 and Cross-Reactive NS1 Antibody. Dengueproteins may also play critical roles in enhancing DVpathogenesis within ECs through a variety of mechanisms.In particular, the NS1 protein is uniquely expressed in threeforms: cytosolic, cell-surfaced expressed, and secreted [47–49]. Soluble secreted NS1 is both highly abundant andhighly antigenic [50]. Likewise, NS1 antibodies are alsopresent in high quantities and have been shown to bind thesurface of platelets and ECs [51]. Because ECs are in steadycontact with blood, they are susceptible to enhanced immunecell targeting promoted by adherent cross-reactive NS1antibodies [51–53]. This targeting, as well as intracellularsignaling triggered by direct NS1 antibody binding, maycontribute to tissue-specific endothelial dysfunction andvascular leakage through EC activation [5, 51–53]. However,despite the abundance of NS1 antibodies that could promoteleakage, vascular permeability is transient and additionalcontributions of NS1 have been poorly explored withinhumans and mouse models. Secreted NS1 can also bindcellular heparan sulfate E present on primary liver and lungECs [54] and, along with the cell surface form of NS1, mayfurther recruit circulating antibodies and immune factors todengue infected ECs [55, 56].

As a secreted protein, the dengue NS1 protein modulatesclassical complement activation by binding to the C4b bind-ing protein, thereby inactivating C4b [57]. Thus, cell-surfaceexpressed NS1 on ECs could serve as a platform for C4binactivation and antagonize classical complement activationpathways. Secreted NS1 may similarly attenuate complementactivation by binding C1s/proC1s and C4 in a complexthat reduces C4 levels required for complement pathwayactivation [58]. Together, NS1 and NS1 antibodies form apotent combination within DHF and DSS patients capableof eliciting or regulating immune and complement responsesthat act on the endothelium and contribute to dengue patho-genesis [59]. Curiously, the alternative complement pathwayactivator complement factor B, transcriptionally induced in

dengue-infected endothelial cells [46], may induce C3a- andC5a-directed chemotaxis and histamine release by bypassingNS1 complement regulation. Antibody targeting of factor D,which activates factor B through cleavage, inhibits comple-ment and leukocyte activation in nonhuman primates andseveral therapeutics have been developed that antagonize C3aand C5a receptor binding [60–63]. These advances suggestthat the alternative pathway may be a new potential targetfor therapeutically reducing the severity of DHF and DSSdiseases. Additional barrier stabilizing effectors that targetthe endothelium may also be considered as a means oftherapeutically reducing vascular leakage and inflammationthat contribute to dengue pathogenesis [64, 65].

3. In Vivo Animal Models ofDengue Virus Infection

3.1. Mouse Models of Dengue Virus Infection. Progress inunderstanding dengue pathogenesis has been hampered bythe lack of suitable mouse models that replicate humancellular tropism and disease symptoms. In normal mice,dengue infection results in limb paralysis and little mortality[31]. Recently mouse-adapted dengue strains that mimicaspects of severe human disease in interferon (IFN) receptorknockout AG129 mice have been used as a dengue virusanimal model [8, 31, 66–68]. Organ damage, hemorrhage,vascular leakage, viremia, and elevated cytokine levels anal-ogous to that in humans are observed following dengueinfection of AG129 mice [66, 67]. In one study, high titerinoculation of mice initiated TNFα-induced apoptosis ofECs, leading to vascular leakage [69]. However, IFN defectivemurine models further complicate our understanding ofthe dengue disease process since they do not fully mimichuman responses to infection and lack IFN responses thatlimit dengue spread and induce EC proliferation and repair.Despite these limitations, current models have provided newinsight into dengue virus pathogenesis and allow for kineticstudies of dengue virus infection of ECs.

Vascular leakage occurs in AG129 mice infected withmouse-adapted dengue strains and several studies haveisolated murine-infected ECs within the spleen and liver[8, 30]. In support of a role for infected ECs in mediatingsevere dengue disease, Zellweger et al. recently reported thatin the presence of subneutralizing levels of dengue-specificantibodies (ADE-mediated infection), a large percentage ofinfected liver sinusoidal ECs (LSECs) were detected andcorrelated directly with disease severity [8]. No evidence forADE-mediated infection of ECs exists in vitro [70], althoughliver sinusoidal cells reportedly express Fcγ receptors thatmay contribute to immune enhanced infection of liver ECs[71]. In the same study, infection of mucosal macrophageswas not enhanced by the presence of dengue antibodies andoccurred after detection of infected LSECs, suggesting thatincreased viral loads from LSEC infection, but not ADE,enhanced immune cell infection [8]. Although a mechanismfor this occurrence has yet to be determined, these findingsgive importance to the role of ECs in mediating denguepathogenesis in the mouse animal model. Therefore, inaddition to increasing viremia, the ability of dengue virus


to infect ECs in vivo may provide a means for infection toalter capillary permeability and induce cytokine responsesfrom ECs that recruit immune cells and contribute to denguepathogenesis.

3.2. Mouse Model Responses Influenced by IFN. Since IFNplays a significant role in the regulation of viral spread andthe growth and repair of the endothelium [3, 72–76], it isimportant to consider the consequences of dengue infectionsoccurring in IFN unresponsive mouse models. Since IFNreportedly stimulates EC proliferation [76], IFN secretion bydengue infected cells is also likely to contribute to vascularrepair following dengue infection, and the absence of theIFN-signaling response may explain the enhanced pathogen-esis of dengue infections in IFN receptor knockout AG129mice [31, 67, 77]. This absence abrogates antiviral responsesthat may naturally curb infection [72, 74]. Likewise, thedengue NS5 protein, which interferes with downstreamIFN signaling to permit virus replication through STAT2degradation, is unable to bind mouse STAT2 [78, 79]. Thesedifferences cloud interpretation of results from dengue-infected mice and may in fact contribute significantly tohemorrhagic responses that may or may not reflect normalpathogenic mechanisms. Current work is ongoing to addressthe lack of IFN responses within mice and create knock-inmice, which harbor functional human STAT2 [79].

3.3. Nonhuman Primate Models. Limited studies have alsobeen conducted on nonhuman primates (NHPs) as an ani-mal model. However, NHPs display almost no human symp-toms of DF/DSS/DHF despite detectable virus replication[80]. Gene profiling following infection in NHPs revealed apotent antiviral response yet, in contrast to humans, almostno production of type I or II interferons or inflammatorycytokines [81]. Thus, murine models still appear to be themost suitable animal model for studying dengue infection,specifically in relation to cellular tropism and EC responses.Further work continues to explore new mouse adaptationsthat may one day produce animal models that fully mimichuman responses to dengue infection.

4. In Vitro Infection of Endothelial Cells

4.1. Use of Endothelial Cell Lines for Studying Dengue VirusInfection. The difficulty of analyzing infections of the en-dothelium in vivo has driven the in vitro exploration ofdengue infection of ECs. In vitro, ECs from various sourcesare permissive for dengue virus infection and have beenused to study pathophysiological changes occurring withinthe endothelium following dengue virus infection. However,not all EC lines are equivalent and this has led to con-fusing and often contradictory results [82, 83]. Cell linesderived from endothelial and epithelial cell fusions are notrepresentative of primary ECs and the ECV304 endothelialcell line has been shown to be bladder carcinoma and notendothelial in nature [84]. However, early passage primaryhuman ECs permit investigation of dengue virus infectionthat approximates the human endothelium for analysis ofdengue-altered EC responses.

4.2. Replication and Receptors for Dengue Virus on ECs. Den-gue virus replicates within HUVECs (human umbilical veinECs), LSECs, HPMEC-ST1.6R cells (human pulmonary ECline), ECV304 (endothelial cell line), and HMEC-1 cells(human microvascular EC line) [26, 27, 70, 85–89]. Recent invitro studies demonstrated that efficient infection of primaryECs by dengue virus occurs as a result of attachment toheparan sulfate-containing cell surface proteins (HSPGs)[88]. HSPGs, specifically heparan sulfate glycoproteins ofsyndecan 2, also mediate attachment of dengue virus toK562 monocytes [90]. Although more specific HSPGs onECs still need to be defined, an EC receptor blockade hasthe potential to reduce viremia, immune targeting of denguevirus infected ECs, and dengue virus-induced changes in ECsthat contribute to pathogenesis.

4.3. Responses Elicited by Dengue-Infected ECs In Vitro. Sev-eral studies have focused on changes in the levels of cellularmolecules or markers of EC activation, including VCAMand ICAM [91, 92]. Dengue virus infection upregulatescell surface markers of EC activation which can trigger theexpression and release of various cytokines, chemokines, andcomplement factors that act on neighboring tissues, ECs,and circulating immune cells. Analysis of dengue-inducedpermeability responses suggested that EC permeability wasincreased in vitro [93]. Although a productive infection wasnot verified in this study, permeability occurred in conjunc-tion with a decrease in VE-cadherin, which regulates the fluidbarrier function of adherens junctions [93, 94].

Additional studies examined the induction or secretionof cytokines following dengue virus infection of primaryHUVECs and ECV304, LSEC-1, HMEC-1, or HPMEC-ST1.6R cell lines [26, 27, 37, 85, 87, 89, 95]. Dengue infectionof the HPMEC-ST1.6R cell line increased IL-6 and IL-8(6–8 days p.i.) as well as vascular endothelial cell growthfactor (VEGF) [27, 95]. Other studies have also singledout RANTES, IL-6 and/or IL-8 as cytokines elicited bydengue-infected ECs [26, 37, 46, 87], thus promoting theendothelium as a source of potent chemotactic cytokines inDSS/DHF patients. Both IL-8 and RANTES are chemotacticagents that can increase vascular permeability by localizedattraction of neutrophils [96, 97]. Analyses of transcriptionalchanges elicited in response to dengue infection also showsmall increases in additional cytokines and antiviral IFN-stimulated genes [27, 37, 46]. IFN is highly induced indengue patients and these findings suggest that ECs are likelyto contribute to circulating IFN responses.

4.4. Kinetics of Dengue Virus Infection In Vitro. Dengue in-fected endothelial cell lines reportedly induce a low level ofinfection (90% uninfectedcells at late time points after infection (3–8 days) makes itdifficult to accurately assess the contribution from dengueinfected cells. This is compounded by innate antiviralresponses elicited by infecting a small number of ECs andthe stimulation of IFN responses by >90% uninfected ECs.

A recent kinetic analysis of primary EC responses todengue virus infection paints an important picture of the


endothelium’s role in dengue disease. Primary EC monolay-ers are ∼80% infected by dengue virus and rapidly producevirus by 24 hours after infection [88]. Both the productionof progeny virus and the number of infected ECs withinmonolayers decrease 2-3 days after infection [88]. Denguevirus titers following EC infection were nearly identical toviral titers observed in IFN-deficient VeroE6 cells [88], sug-gesting that virus regulates early cellular interferon responsesof ECs. In fact, the lack of viral spread reported in somestudies, where fewer than 10% of ECs were infected [37, 70],is consistent with the paracrine effect of interferon producedby a small number of initially infected cells. Thus, in vitrostudies point to the infected endothelium as a likely source ofviremia following dengue virus infection. These findings alsohighlight the importance of assessing the impact of EC infec-tions at early times following in vivo infection, somethingmore easily achieved within mouse models than patients.

Recovering DHF patients regain normal endothelialfunction quickly, implying a transient effect and early recov-ery of EC functions following infection [3]. A rapid pro-ductive infection of the endothelium is difficult to assess inhumans, but in vitro studies show that infected ECs rapidlyrelease virus. This suggests that dengue infected ECs maycontribute to early viremia in dengue patients and presentdengue virus antigens on EC surfaces that may be targeted byimmune cells [88]. Infected ECs may also elicit cytokine andchemokine responses that can act directly on the endothe-lium [26, 27, 37, 85, 87, 89, 95]. Endpoint sampling of ECs atautopsy or analysis of endothelial function within recoveringpatients does not take into consideration an early or transientinfection of ECs as is observed in vitro. The lack of apparentspread within EC monolayers and the apparent decrease ininfected cells 2-3 days after infection [46] also suggest thatEC-elicited IFN responses may limit dengue virus spreadin vitro and contribute to high levels of circulating IFNin dengue patients. Interestingly, IFN treatment directs ECproliferation and may be a response that both limits viralspread and activates the EC repair process [76]. In fact, ECproliferation in response to IFN may explain the absence ofendothelial damage within DHF patients and the presence ofvascular leakage in IFN receptor deficient mouse models.

5. Conclusions

The endothelium is not a static channel that simply sepa-rates the vasculature from surrounding tissue [33–35]. Theendothelium dynamically elicits responses that may con-tribute to immune enhancement and vascular permeabilityduring dengue virus infection. Several hypotheses have beenoffered to explain the development of severe dengue diseaseand immune enhanced responses clearly impact barrierfunctions of the endothelium, but pathogenic mechanismsthat result in DHF and DSS remain vague [1–3, 26]. Leakageof the vascular endothelium is a central component ofdengue virus disease and studies discussed here suggestthat the dengue infected endothelium may contribute topathogenic immune responses and immune targeting of theendothelium. However, the role of dengue virus infectedECs in pathogenesis requires definitive in vivo kinetic studies

which are difficult to perform in patients. The ability ofthe endothelium to respond to immune cells resulting incapillary permeability further highlights the importance ofdengue infected ECs in pathogenesis. The central importanceof the endothelium in dengue disease suggests that stabilizingfluid barrier functions of the endothelium may be a thera-peutic approach for reducing vascular leakage in DHF andDSS patients [64, 65].

Acknowledgments

The authors thank Irina Gavrilovskaya, Valery Matthys,and Elena Gorbunova for critical paper review and help-ful discussions. This work is supported by NIH, NIAIDGrants R01AI47873, PO1AI055621, R21AI1080984, andU54AI57158 (NBC-Lipkin).

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